Structure‐Function Relationships in the Complexation of Steroids by a Synthetic Receptor

The complexation between the double‐decker cyclophane (±)‐ 1 and a series of 30 steroids was investigated in CD 3 OD by 1 H‐NMR titrations. The geometries of the complexes, in which the substrates are axially included in the 13‐Å deep and 9 Å×12 Å wide receptor cavity, were estimated based on the complexation‐induced changes in chemical shift (CIS) of the steroidal Me group resonances. Computer modeling provided additional support for the geometries deduced from the experimental data. The log  P (octanol/H 2 O) values of the steroids were determined experimentally by HPLC or calculated using the program CLOGP. Although steroids with a high log  P form some of the most stable complexes with (±)‐ 1 , a general correlation between the thermodynamic driving force for association − Δ G 0 and the partition coefficient was not observed. It can, therefore, be concluded that inclusion complexation is not only driven by the preference of the steroid to transfer from the polar solvent into the lipophilic binding cavity but also by specific host‐guest interactions. A series of structure‐function relationships was revealed. i ) Steroids with an isoprenoidal side chain at C(17) form some of the most stable complexes (− Δ G 0 up to 4.8 kcal mol −1 ), with side‐chain encapsulation contributing as much as 1.2 kcal mol −1 to the association strength. In these complexes, the receptor is slipping in a dynamic process over both the tetracyclic core and the lipophilic side chain. ii ) Pregnane derivatives, which lack the isoprenoidal side chain, are tightly encapsulated with their tetracyclic core. Upon introduction of double bonds, the core flattens, and binding affinity drops substantially. iii ) The presentation of steroidal OH groups to the receptor cavity is accompanied by energetically unfavorable functional‐group desolvation, which strongly reduces the host‐guest binding affinity. In contrast, inclusion of steroidal carboxylate or keto groups into the cavity does not substantially change complexation strength as compared to the unsubstituted derivatives. iv ) Addition of extra Me groups to the steroidal A ring does not have a large effect on the association strength; however, complex geometries may change significantly. v ) Receptor (±)‐ 1 shows a remarkably high affinity towards progesterone (− Δ G 0 =4.7 kcal mol −1 ) despite the low log  P value (3.87) of this steroid. Small changes in the progesterone structure lead to large reductions in complex stability, which clearly demonstrates that the double‐decker cyclophane is a selective molecular receptor.